Periventricular white matter injury is the major form of brain injury in the premature infant and underlies the development of cerebral palsy. The predilection of the premature infant to white matter injury appears to be related to maturation-dependent vulnerability of the oligodendrocyte (OL) lineage. We will employ a novel neural stem cell-based tissue culture system that generates large numbers of highly enriched OL progenitors to test the hypothesis that maturation-dependent responses to oxidative stress are related to the particular susceptibility of OL progenitors to cell death. Oxidative stress will be generated using oxygen and glucose deprivation (OGD), a well established in vitro model of hypoxia-ischemia. We will define perturbations in cell signaling pathways that occur in response to OGD. The insulin-like growth factors (IGFs) are potent neuroprotective agents that are crucial for the survival of the OL lineage. Perturbations in IGF signaling in response to OGD will be related to OGD-mediated alterations in the efficacy of IGF to promote survival. We will test the overall hypothesis that oxidative stress-induced OL death and survival is related to alterations in cell signaling that enhance pro-survival pathways and suppress the activation of cell death pathways.